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  N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody

Zibat, A., Zhang, X., Dickmanns, A., Stegmann, K., Dobbelstein, A., Alachram, H., et al. (2023). N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody. iScience, 26(10): 107786. doi:10.1016/j.isci.2023.107786.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000D-BFAA-D Version Permalink: https://hdl.handle.net/21.11116/0000-000D-BFAB-C
Genre: Journal Article

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 Creators:
Zibat, A., Author
Zhang, X., Author
Dickmanns, A., Author
Stegmann, K.M., Author
Dobbelstein, A.W., Author
Alachram, H., Author
Soliwoda, R., Author
Salinas, G., Author
Groß, U., Author
Görlich, D.1, Author           
Kschischo, M., Author
Wollnik, B., Author
Dobbelstein, M., Author
Affiliations:
1Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350135              

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 Abstract: N4-hydroxycytidine (NHC), the active compound of the drug Molnupiravir, is incorporated into SARS-CoV-2 RNA, causing false base pairing. The desired result is an “error catastrophe,” but this bears the risk of mutated virus progeny. To address this experimentally, we propagated the initial SARS-CoV-2 strain in the presence of NHC. Deep sequencing revealed numerous NHC-induced mutations and host-cell-adapted virus variants. The presence of the neutralizing nanobody Re5D06 selected for immune escape mutations, in particular p.E484K and p.F490S, which are key mutations of the Beta/Gamma and Omicron-XBB strains, respectively. With NHC treatment, nanobody resistance occurred two passages earlier than without. Thus, within the limitations of this purely in vitro study, we conclude that the combined action of Molnupiravir and a spike-neutralizing antagonist leads to the rapid emergence of escape mutants. We propose caution use and supervision when using Molnupiravir, especially when patients are still at risk of spreading virus.

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Language(s): eng - English
 Dates: 2023-08-302023-10-20
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.isci.2023.107786
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Project name : This work was funded by the VolkswagenStiftung (AZ 9A827) to M.D. and D.G. as well as AZ 9B785 to M.D., by the COVID-19 Forschungsnetzwerk Niedersachsen (COFONI) to M.D., the German Federal Ministry of Education and Research (BMBF) to M.K., and by a grant from the Max-Planck-Foundation to D.G. X.Z. was supported by a grant from the Ministry of Science and Health of Rhineland-Palatinate, Germany (COVID-AI).
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Title: iScience
Source Genre: Journal
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Publ. Info: Amsterdam ; Bosten ; London ; New York ; Oxford ; Paris ; Philadelphia ; San Diego ; St. Louis : Elsevier
Pages: - Volume / Issue: 26 (10) Sequence Number: 107786 Start / End Page: - Identifier: ISSN: 2589-0042
CoNE: https://pure.mpg.de/cone/journals/resource/2589-0042